Bloom's Syndrome (BS) is a rare autosomal recessive disorder defined by growth deficiency, immunodeficiency, and a predisposition to early onset of cancers of all types. Earlier studies documented chromosome breaks, rearrangements, somatic mutations, and an elevated rate of sister-chromatid exchanges in cells from affected individuals. This high level of genomic instability leads to mutations at multiple critical genomic sites and the high rate of neoplasia. The PI's laboratory has isolated the Bloom's Syndrome gene (BLM) by genetic mapping and positional cloning. An investigation of the activities of the wild-type and mutant BLM gene products will be important in our understanding of how the mutated genes influence the clinical phenotype and how chromosome instability occurs in human somatic cells. The PI's proposal presents investigations into the genetic and biochemical activities of the BLM gene product and an attempt to use the experimental precision of yeast genetics to begin its functional characterization. The PI's work will constitute the first steps toward elucidating the role of the BLM gene product in maintaining genetic fidelity in human somatic cells and how its mutation leads to the clinical phenotype of Bloom's Syndrome.